If the endocrine activity of the gonads decreases or if the gonads are removed, women and dogs show similar changes. With the reproductive senescence in women, as well as after ovarectomy in the bitch, symptoms such as urinary incontinence, vasomotor symptoms, in particular hot flushes, changes of the mood, skin and hair increasingly occur. After ovarectomy, as well as at the beginning of the reproductive senescence, corresponding hormonal changes occur with a great increase in serum concentrations of FSH (Follicle stimulating hormone) and LH (Luteinising hormone).
1. Urinary Incontinence in General
Urinary incontinence is defined by the International Continence Society [1] as the objective demonstration of involuntary loss of urine consequent to bladder and/or urethral sphincter dysfunction.
If the anatomical conditions are normal, two different pathophysiological mechanisms can lead to urinary incontinence: an increased tone of the bladder with a normal closure function of the urethra, or an insufficient closure function of the urethra with a normal bladder pressure during the filling phase.
An insufficient closure function of the urethra plays a crucial role in both the urinary incontinence in bitches due to spaying and the stress incontinence in women [2] [3] [4].
2. Removal of the Ovaries (Spaying) in the Bitch
Side Effects
Gonadectomy can lead to side effects. The most common is urinary incontinence, which occurs in one in five spayed bitches. The continuous hair loss, which is due to the shortened life span of the hairs after spaying, can be disturbing to the owner. Less common, and mainly in particular breeds, is the excessive growth of the undercoat which leads to a “baby-coat”. If food is offered ad libitum the increased appetite can lead to adipositas and vulvapyodermia. In case of dominant bitches gonadectomy may increase aggressivity.
Endocrine Principles
Twice per year the bitch is on heat for about 3 weeks. Her seasonal mono-oestrous cycle is divided into 4 periods, anestrus, pro-oestrus, oestrus and metoestrus. During anoestrus the plasma concentrations of sexual steroids are very low. The level of progesterone is below 1 ng/ml, and that of estrogen is below 10 pg/ml. Towards the end of anoestrus, about four weeks before the onset of the next heat, slight increases in estradiol concentrations can be measured. At the onset of the heat, starting with pro-oestrus, the internal secretion of estradiol is slightly increased by the growing follicles. At the end of pro-oestrus a sudden increase of the internal estradiol secretion occurs over two to three days, resulting in a peak serum estradiol of 40 to 90 pg/ml. During the pro-oestrous period the follicular growth is stimulated by pulsatile FSH and LH release and 24 to 72 hours after the last LH-peak ovulation is triggered. The actual oestrus, which is characterized by the bitch's acceptance of the male dog, is dominated by an increasing serum progesterone concentration, whereas the estrogen level returns to basal concentrations of less than 10 pg/ml. The corpora lutea produce progesterone for about three months. The progesterone production is independent of whether the bitch is pregnant or not pregnant. The luteal phase is called metoestrus. After the luteolysis, serum progesterone levels are below 1 ng/ml, the bitch is in the period of ovarian quiescence, the anoestrus. During this period the average concentrations of the gonadotropins FSH and LH are about 114 ng/ml and 1.1 ng/ml respectively [5]
With gonadectomy the source of the sexual steroids estrogen and progesterone is removed and afterwards, they are only measurable in very low serum concentrations that are not different from those measured during anoestrus. As there is no longer a feed back mechanism, FSH and LH are secreted unhindered, resulting in average concentrations of 1086 ng/ml and 7.4 ng/ml respectively [5]
Relationship Between Endocrine Changes and Side Effects of Gonadectomy
Until now, the side effects of spaying have been explained as resulting from the missing estrogen secretion. But various observations do not agree with this hypothesis. In sexual intact bitches the endogenous estrogen concentration is elevated only for a short period only once or twice per year. In many bitches which are treated with depot gestagens for suppressing of the estrous cycle for years, the endogenous estrogen concentration is permanently reduced to basal levels. In these bitches with a permanently suppressed ovarian activity most of the side effects seen after spaying, in particular urinary incontinence, do not occur. If low estrogen concentrations would be responsible for the occurrence of urinary incontinence, it could be assumed that the replacement therapy with estrogens would be successful, but in fact, it is effective only in 65% of the cases [6]. Conversely, it would be expected that in sexually intact bitches urinary incontinence does not occur, especially not during the heat. Apart from the many incontinent bitches, due to spaying, seen as patients at the Department of Reproduction, University of Zurich, there are several intact bitches which are incontinent exclusively during estrus. Urodynamic data supports these observations, showing a significantly reduced urethral closure pressure under the influence of estrogens, during the estrus.
Urinary Incontinence of the Bitch
Urinary incontinence is the most common and embarrassing side effect of spaying for both the owner and the dog [3]. In all bitches gonadectomy leads to a significant reduction in the urethral closure pressure within one year. In 20% of the bitches the urethral closure pressure drops below the critical threshold value of 7.5 cm H2O, leading to urinary incontinence [3]. Urinary incontinence also has medical consequences: Due to the lowered urethral closure function the ascension of bacteria, leading to an urinary tract infection, is enhanced. Additionally, the continuous contamination of the perineal region with urine can result in skin ulceration.
Therapy is aimed at improving the urethral closure pressure which can be achieved by conservative or surgical methods. First choice are alpha-adrenergic substances such as ephedrinhydrochloride or phenylpropanolamine, at 1.5 mg/kg BW p.o. two to three times per day. If these medications are given every 8 hours, continence was achieved in 74%, and at least 24% showed some improvement. But, for the owner it is not always possible to administer tablets this frequently. Side effects such as diarrhea, vomiting, anxiety and nervousness are observed only infrequently. Alpha-adrenergic substances are contraindicated in case of glaucoma, cardiac arrhythmia and progressive nephropathy. As an alternative therapy estrogens can be used, which improve the responsiveness of catecholamine receptors of the urethra. But given alone, their effectiveness is inferior to that of the alpha-adrenergic substances, for they were found ineffective in 24% of the cases [3]. The substitution with estrogens in dogs can lead to a bone marrow depression, which can be fatal. Quite a common side effect of the estrogen therapy is recurrence of heat-like symptoms and with it sexual attractiveness to male dogs. These side effects can even be observed after therapy with phytoestrogens.
If therapy with medication is unsuccessful, too much trouble to the owner, accompanied with side effects, or even contraindicated, a surgical or endoscopic procedure can be considered. The injection of collagen into the submucosa of the proximal urethra, under endoscopic control, is successful in 75% of the cases and can be repeated if necessary. But this therapy requires a full anesthesia, it is expensive and its success is dependent on the experience of the surgeon. Even more invasive, and therefore expensive, is a surgical method, the classical retropubic urethropexy for incontinent women [7] which has been adapted for dogs [8]. This colposuspension, which is performed in full anesthesia after laparotomy, is only effective in 53% of the dogs with continence [9].
3. Reproductive Senescence in Women
Occurrence
Declining reproductive function is an inevitable part of the aging process [10]. The dramatic endocrine changes brought about by reproductive senescence have biological, social and cultural implications that profoundly influence the latter half of a woman's life.
Symptoms
Women may experience a number of symptoms such as hot flushes, mood changes and altered sleep pattern during the transition from the reproductive to the non-reproductive stage of life. Menopause is associated with an accelerated bone loss which may lead to the development of osteoporosis in women. Vaginal dryness with its sequelae, such as urogenital infections and impaired sex life, are well known problems of menopause. The incidence of urinary tract infections increases in women with increasing age.
Correlation Between Endocrine Changes and Symptoms of the Reproductive Senescence
As one of the first signs of the impending transition to menopause, in middle aged regularly menstruating women, the frequency of LH pulses decreases and the width of the peak increases before any change in the amount of plasma estradiol [11]. These changes are accompanied by elevated FSH concentrations during the early follicular phase [12] [13] [14].
Following, on the one hand there is a continuous increase of serum PSH and LH, while on the other hand a concomitant decrease in estradiol and estrone can be observed, as yearly examinations of women have shown during the transition from the reproductive to the non-reproductive stage of life [15]. Initial symptoms of the reproductive senescence, such as hot flushes and sweating, already occur in normocycling women and were significantly associated with high levels of FSH and LH and with low levels of estradiol [16]. Exacerbation of the symptoms was consistent with changes in gonadotropin levels [17] [18].
Urinary Incontinence in Women
Urinary incontinence also affects many women of all age groups. The prevalence of incontinence has been estimated to be between 9 and 74% [19] [20] [21] [22] [23] [≧] [25].
Until now, the etiology of urinary incontinence is not elucidated, but most likely is caused by several factors. Different studies have shown a correlation between the risk of urinary incontinence and age [26], number of births [20], age of giving birth [25], body mass index [23] [25], race [23] level of education [25], frequency of bed-wetting during childhood [25], physical exercise or menopausal estrogen deficiency [12]. With the development of menopause the frequency of lower urinary tract symptoms, such as urgency, hesitancy and frequency, seem to increase. [27]
The difference of the mean maximum urethral closure pressure is 20 cm H2O between continent and incontinent women of corresponding age. The closure function of the urethra deteriorates in an age dependent relationship in a similar way in continent as well as incontinent women, but is based on different initial values [28] [29] [2] [30].
Urinary incontinence predisposes to urinary tract infections, pressure ulcers, perineal rashes, and urosepsis.
4. Comparison of the Reproductive Senescence in Women and the Side Effects of Spaying in the Bitch
The symptoms associated with reproductive senescence in women have amazing similarities with the side effects of spaying in the bitch. In both species there is an increased incidence of vaginal dryness, mood and behavioral changes, and urinary incontinence. A characteristic feature of urinary incontinence in women, as well as in dogs, is a reduced urethral closure function. In the bitch, spaying is proven to be the trigger for urinary incontinence.
Until now, neither the pathophysiological correlation between spaying and urinary incontinence in the bitch nor the cause of urinary incontinence in women is elucidated. But it can be assumed that similar mechanisms are involved, because for conservative treatment the same substances are recommended in both species.
In reproductive senescence in women as well as after spaying of bitches the levels of FSH and LH increase many times. Because LH receptors are not limited to the genital tract [31] [32] but are also found, among others, in the urinary bladder [33] and the skin [34], a correlation between the increased FSH- and LH levels and the clinical changes after menopause or spaying is most likely. In post menopausal women the number of LH receptors in the bladder decreases, most likely because of a down-regulation of the LH receptors by increased gonadotropin levels [33]. A down-regulation of receptors is also known to occur on a higher level, for example the pituitary gland. Prolonged exposure of GnRH receptors to GnRH results in loss of responsiveness to the hormone, through receptor alteration [35]. The outcome of such a down-regulation of sensitivity to GnRH results in a suppression of circulating levels of gonadotropins [36] [37] [38] [39] [40] [41].
Despite recent progress in understanding the pathophysiology of urinary incontinence, successful management continues to be a challenge. Medical treatment for urinary incontinence in women, or urinary incontinence in the bitch, include estrogen and/or progesterone replacement, supplementation with alpha-adrenergic agonists, beta-adrenergic receptor blocking agents, cholinergic receptor blocking compounds, cholinergic receptor stimulating drugs, nitric oxide synthase substrates, nitric oxide donors or both. Other treatment procedures include behavioral therapy, nerve stimulation, injection therapy, mechanical devices [42] [43] and surgery.
The hitherto existing medical treatments for incontinence have either unsatisfactory success or show severe side effects and can therefore not be administered to patients with e.g. glaucoma, hypertonia and cardiac arrhythmias. Therefore there exists a great need in effective pharmaceutical compositions and medicaments for the successful treatment or prevention of incontinence in female mammals with minimal adverse effects on the treated individual.
It has now surprisingly been found that a compound, or a pharmaceutical composition comprising a compound that modulates the level of biologically active gonadotropins is an effective medicament for the treatment or prevention of urinary incontinence in female mammals.